Male circumcision has been shown in several clinical trials to reduce the risk of a man becoming infected with HIV from his female partner. We do not yet understand the biology of how circumcision works to prevent HIV entering through the penis. Most theories are based on work with foreskin tissues and removal of the foreskin eliminating the risk of HIV infection. However, circumcision does not provide complete protection from HIV infection, making it imperative that we identify all possible sites involved in HIV transmission through the penis. No studies to date have evaluated differences in the glans penis between circumcised and uncircumcised men. Our recent studies in living subjects have found that the glans skin of uncircumcised men is significantly less well protected from the environment than that of the circumcised man. The barrier integrity of the uncircumcised glans skin also fluctuates substantially, perhaps related to greater inflammation and turnover of cells in the skin. This increased inflammation may then lead to a higher likelihood that HIV can enter the uncircumcised glans skin to cause infection. We have also seen that HIV is more capable of meeting a cell that it is able to infect in the uncircumcised glans skin than other penile skin (through studies with tissues obtained from deceased men who have donated their bodies to science). This proposal seeks to obtain glans, shaft, and foreskin penile skin from living subjects through superficial shave biopsies. These biopsies are minimally invasive and naturally heal within a few days-many volunteers have already been recruited and we include preliminary data from two subjects. These samples will be important in resolving issues with penile skin obtained from cadaveric donors, such as tissue degradation after removal from the deceased donor. It will also allow us to properly study cells and proteins in the penile skin that contribute to the risk of HIV infection in the man. Furthermore, we will establish connections between these basic biological characteristics to non-invasive measures of water loss and water content of the penile skin in the living subject to understand how certain men (uncircumcised versus circumcised, those with other underlying sexually transmitted infections versus those without) are at greater risk for HIV infection. This is particularly important as we do not yet fuly know how other sexually transmitted infections such as herpes simplex virus or human papillomavirus contribute to HIV transmission. Establishing bridges between circumcision, other sexually transmitted infections, skin biology and barrier integrity, and susceptibility to HIV willlay the groundwork for future studies aimed at controlling these risk factors to prevent HIV infection in men.